The mating behavior of Saccharomyces cerevisiae (yeast) represents one of the simplest systems of fundamental interest in the study of cell-cell interaction. The signal for mating (or fusion) of cells of opposite mating types a and alpha is mediated by the mating type specific polypeptide pheromones, the a and alpha factors. We propose to clone the alpha-factor structural gene by a two-step procedure involving a preliminary enrichment for clones carrying alpha-specific mRNA sequences, followed by a final screening with a chemically synthesized oligonucleodtide probe. The first step relies on the demonstration by Thorner et al. that a/alpha diploids do not synthesize alpha factor, whereas alpha cells do. Therefore, alpha-specific clones can be identified by prehybridization with cold a/alpha mRNA, followed by hybridization with labeled alpha-cell mRNA. The second screening stage is possible because the amino acid sequence of the alpha-factor is known. This allows the deduction of the DNA sequence of the gene. Due to the ambiguity of the genetic code, four 14-mers, each differing from one another by one base change, will be synthesized. Alternately, we propose to clone the alpha-factor structural gene by direct screening from a bank of yeast DNA cloned in phage M13 with the four 14-mers as probes. After the alpha-factor gene has been cloned, it will be possible to apply the modern techniques of molecular biology to genetically map the alpha-factor gene, to construct essential mutants in this gene, to isolate and characterize alpha-factor mRNA, and to study the regulatory sequences of an alpha-specific gene controlled by the alpha-mating type locus (MAT).